The CNS contains circuitry which can inhibit pain, thereby producing analgesia. This pain inhibitory circuitry can be activated by acute exposure of the organism to aversive/stressful environmental stimuli. Animals can also learn cues that predict that they will be exposed to aversive/stressful environmental stimuli, & become analgesic in response to these cues, called danger signals. Observations such as these led to the widely held view that the physiological function of such circuitry is to suppress pain during threatening situations, since pain perception at such a time would compromise efficient defense/escape behavior. Recent evidence strongly suggests the existence of neural circuitry with a function opposing that described above. That is this circuitry appears to specifically block analgesia, thereby producing anti-analgesia. To date, this blockade has been found only for opiate analgesias. Therefore it is possible that this is a specific "anti-opiate analgesia" system. A number of candidate anti-opiate analgesia neurotransmitters have been identified (e.g., CCK & FMRFamide). Injection of receptor agonists of such substances blocks opiate analgesias whereas receptor antagonists can markedly enhance the onset, peak effect & duration of a variety of opiate analgesic states. In addition to being able to learn danger signals, animals can learn cues that predict the non-occurrence of aversive events. For example, they can learn a light cue that signals that shock will not occur for a period of time. Thus, the light cue serves as a safety signal. It is now known that safety signals activate anti-opiate analgesia. That is, various opiate analgesias, including systemic & spinal morphine analgesias, are abolished by presentation of the safety signal. It is clear from these dramatic data that an understanding of endogenous anti-analgesia systems that function to oppose opiate analgesia may potentially provide novel approaches for the control of pain. The aim of the present proposal is to investigate the endogenous mechanisms underlying anti-analgesia. Dose-response studies will characterize the effect of the safety signal on opiate & non-opiate drug- & stress-induced analgesias, & will identify anti-analgesic substances mediating these effects. Time-response studies will characterize the development & duration of anti-analgesia. Generality of the safety signal effects will be examined by varying the stimulus used as the safety signal, by varying the conditioning parameters, & by varying the pain measures. By addressing well-defined, basic questions the proposed studies should provide major insights into the mechanisms underlying this newly discovered neural circuitry.